Abstract
Lyme disease, the most common vector-borne illness in North America, is caused by the spirochete Borrelia burgdorferi. Infection begins in the skin following a tick bite and can spread to the hearts, joints, nervous system, and other organs. Diverse host responses influence the level of B. burgdorferi infection in mice and humans. Using a systems biology approach, we examined potential molecular interactions between human extracellular and secreted proteins and B. burgdorferi. A yeast display library expressing 1031 human extracellular proteins was probed against 36 isolates of B. burgdorferi sensu lato. We found that human Peptidoglycan Recognition Protein 1 (PGLYRP1) interacted with the vast majority of B. burgdorferi isolates. In subsequent experiments, we demonstrated that recombinant PGLYRP1 interacts with purified B. burgdorferi peptidoglycan and exhibits borreliacidal activity, suggesting that vertebrate hosts may use PGLYRP1 to identify B. burgdorferi. We examined B. burgdorferi infection in mice lacking PGLYRP1 and observed an increased spirochete burden in the heart and joints, along with splenomegaly. Mice lacking PGLYRP1 also showed signs of immune dysregulation, including lower serum IgG levels and higher levels of IFNγ, CXCL9, and CXCL10.Taken together, our findings suggest that PGLYRP1 plays a role in the host’s response to B. burgdorferi and further demonstrate the utility of expansive yeast display screening in capturing biologically relevant interactions between spirochetes and their hosts.
Highlights
Lyme disease is the most common tick-borne illness in North America
It is important to have efficient methods to be able to identify the various components of the immune system that interact with B. burgdorferi to better understand the disease process, but few currently exist
We identified Peptidoglycan Recognition Protein 1 (PGLYRP1), an innate immune protein important in defense against bacteria, as a major candidate from this screen
Summary
Lyme disease is the most common tick-borne illness in North America. The causative spirochete Borrelia burgdorferi is primarily transmitted by Ixodes scapularis ticks [1]. The pathogenesis of Lyme disease is multifactorial, involving both bacterial components that influence virulence, dissemination and infectivity, and host factors that are responsible for inflammation and the modulation of infection [4,5]. Some of the surface displayed lipoproteins are immunogenic and are involved in the pathogenesis of Lyme disease. PG, including that of B. burgdorferi [11], can be recognized by host pattern recognition receptors and stimulate immune responses [14]. The mammalian immune response to B. burgdorferi involves both humoral and cell-mediated factors that help to control or eliminate spirochetes [15,16,17]. There is a critical need to identify specific host immune proteins that interact with spirochete components, including lipoproteins, flagellar proteins, peptidoglycan and glycolipids
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